The International Risk Governance Council (IRGC) was a nonprofit foundation, based first as an independent, freestanding Swiss foundation in Geneva from 2003 to 2012, and then affiliated with École Polytechnique Fédérale de Lausanne in Lausanne from 2012 to 2023. IRGC's mission was to identify and improve the governance of emerging and systemic risks that have, or could have, impacts on human and environmental health, the economy and society, and overall sustainability. In this paper, we recount IRGC's history, describe its many reports, workshops, and conference activities (including tables referencing the many published products), and provide six brief case histories of accomplishments and insights on work IRGC has done on solar radiation management, small modular reactors, synthetic biology, autonomous vehicles, resilience and systemic risks, and international comparison of risk governance. The paper concludes with some brief observations about the impact of IRGC's work and notes the continuing need for a neutral convening entity that can perform a role similar to that of IRGC.

Clinicians and patients often try a treatment for an initial period to inform longer‐term therapeutic decisions. A more rigorous approach involves N‐of‐1 trials. In these single‐patient crossover trials, typically conducted in patients with chronic conditions, individual patients are given candidate treatments in a double‐blinded, random sequence of alternating periods to determine the most effective treatment for that patient. However, to date, these trials are rarely done outside of research settings and have not been integrated into general care where they could offer substantial benefit. Designating this classical, N‐of‐1 trial design as type 1, there also are new and evolving uses of N‐of‐1 trials that we designate as type 2. In these, rather than focusing on optimizing treatment for chronic diseases when multiple approved choices are available, as is typical of type 1, a type 2 N‐of‐1 trial tests treatments designed specifically for a patient with a rare disease, to facilitate personalized medicine. While the aims differ, both types face the challenge of collecting individual‐patient evidence using standard, trusted, widely accepted methods. To fulfill their potential for producing both clinical and research benefits, and to be available for wide use, N‐of‐1 trials will have to fit into the current healthcare ecosystem. This will require generalizable and accepted processes, platforms, methods, and standards. This also will require sustainable value‐based arrangements among key stakeholders. In this article, we review opportunities, stakeholders, issues, and possible approaches that could support general use of N‐of‐1 trials and deliver benefit to patients and the healthcare enterprise. To assess and expand the benefits of N‐of‐1 trials, we propose multistakeholder meetings, workshops, and the generation of methods, standards, and platforms that would support wider availability and the value of N‐of‐1 trials.

Gene drives have already challenged governance systems. In this case study, we explore the International Genetically Engineered Machine (iGEM) competition's experiences in gene drive-related research and lessons in developing, revising, and implementing a governance system. iGEM's experiences and lessons are distilled into 6 key insights for future gene drive policy development in the United States: (1) gene drives deserve special attention because of their potential for widescale impact and remaining uncertainty about how to evaluate intergenerational and transboundary risks; (2) an adaptive risk management approach is logical for gene drives because of the rapidly changing technical environment; (3) review by individual technical experts is limited and may fail to incorporate other forms of expertise and, therefore, must be complemented with a range of alternative governance methods; (4) current laboratory biosafety and biosecurity review processes may not capture gene drive research or its components in practice even if they are covered theoretically; (5) risk management for research and development must incorporate discussions of values and broader implications of the work; and (6) a regular technology horizon scanning capacity is needed for the early identification of advances that could pose governance system challenges.

Biotechnology innovation has never been more accessible to individuals, companies, and (research)organizations. Advances in genetic engineering, declining costs, and improved education have improved access to biotechnologies. Such openness has provided many benefits as biotechnology has been used to address some of the world’s most intractable problems However, increased access to biotechnology tools and knowledge may also pose risks to humans, animals, and the environment (Meyer 2013; Kera 2014; Li et al. 2017; Oye 2012).

We must ensure that trials are scientifically, politically, and socially robust, publicly accountable, and widely transparent

The fast-paced field of synthetic biology is fundamentally changing the global biosecurity framework. Current biosecurity regulations and strategies are based on previous governance paradigms for pathogen-oriented security, recombinant DNA research, and broader concerns related to genetically modified organisms (GMOs). Many scholarly discussions and biosecurity practitioners are therefore concerned that synthetic biology outpaces established biosafety and biosecurity measures to prevent deliberate and malicious or inadvertent and accidental misuse of synthetic biology's processes or products. This commentary proposes three strategies to improve biosecurity: Security must be treated as an investment in the future applicability of the technology; social scientists and policy makers should be engaged early in technology development and forecasting; and coordination among global stakeholders is necessary to ensure acceptable levels of risk.

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real-world conditions with longer follow-up periods. In "efficacy-to-effectiveness (E2E) trials," if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an "efficacy and effectiveness too (EE2) trial." Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort.

Governance is a broader and more flexible concept than statute-driven regulations as it incorporates components outside the latter's remit. Considerations of governance are critical in the development of emerging biotechnologies such as gene drive organisms. These have been proposed or are being developed to address public and environmental health issues not addressed easily by conventional means. Here, we consider how the concept of governance differs from statute-driven regulation with reference to the role each may play in the development of gene drive organisms. First, we discuss existing statute-based regulatory systems. Second, we consider whether novel risks or different concerns derive from gene drive organisms, concentrating on characteristics that contribute to public health or environmental risk and uncertainties that may affect risk perceptions. Third, we consider public engagement, outlining how existing statute-driven regulatory systems and other governance mechanisms may provide opportunities for constructive interactions. Finally, we provide some observations that may help address science - and values-based concerns in a governance space larger than that of statute-driven regulatory systems.

The deployment of gene drives is emerging as an alternative for protecting endangered species, controlling agricultural pests, and reducing vector-borne diseases. This paper reports on a workshop held in February 2016 to explore the complex intersection of political, economic, ethical, and ecological risk issues associated with gene drives. Workshop participants were encouraged to use systems thinking and mapping to describe the connections among social, policy, economic, and ecological variables as they intersect within governance systems. In this paper, we analyze the workshop transcripts and maps using the Institutional Analysis and Development (IAD) framework to categorize variables associated with gene drive governance and account for the complexities of socio-ecological systems. We discuss how the IAD framework can be used in the future to test hypotheses about how features of governance systems might lead to certain outcomes and inform the design of research programs, public engagement, and anticipatory governance of gene drives.

To celebrate the anniversary of an arcane federal guideline is a rare event. For an agency to use that moment to invite reflection on modifying policies is even rarer. Last month, the U.S. National Institutes of Health (NIH) did just that, with a workshop that marked the 40th anniversary of its Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. The meeting was an inspiring start for charting future oversight of nonclinical applications.

This report presents a study commissioned by the European Parliament to compare regulatory standards in the EU and the US in four key sectors (food safety, automobiles, chemicals, and pharmaceuticals), chosen for their relevance both to consumer protection and transatlantic trade, and focusing on whether different approaches to risk regulation may lead to different levels of protection. How risks are regulated in the US and the EU can affect domestic outcomes (such as the benefits and costs of protecting consumers, health and environment), and can also foster or limit the opportunities for international trade.

This article describes recent developments in licensing and reimbursement policies in the EU, US, and Japan, examines causes of changes and compares differences and projects trends. With respect to licensing, the European Medicines Agency (EMA), US Food and Drug Administration (FDA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) are committed to rigorous evaluation of pharmaceuticals in advance of market access with feedback from postmarket experience. The EMA is exploring integrated adaptive pathways for licensing, with formal pilot tests to provide a practical proof of concept. The FDA is augmenting traditional licensing procedures through reforms including Breakthrough Product Designation. The PMDA is implementing reforms to foster innovation and earlier patient access through its Sakigake strategy and licensing reforms on regenerative medicines. With respect to reimbursement, several generalizations emerge. Relative to US counterparts, EU payers typically set higher standards for evidence of effectiveness as a condition of reimbursement, impose tougher limits on reimbursement by indication, and drive harder deals in negotiations over prices.

The current system of biomedical innovation is unable to keep pace with scientific advancements. We propose to address this gap by reengineering innovation processes to accelerate reliable delivery of products that address unmet medical needs. Adaptive biomedical innovation (ABI) provides an integrative, strategic approach for process innovation. Although the term "ABI" is new, it encompasses fragmented "tools" that have been developed across the global pharmaceutical industry, and could accelerate the evolution of the system through more coordinated application. ABI involves bringing stakeholders together to set shared objectives, foster trust, structure decision-making, and manage expectations through rapid-cycle feedback loops that maximize product knowledge and reduce uncertainty in a continuous, adaptive, and sustainable learning healthcare system. Adaptive decision-making, a core element of ABI, provides a framework for structuring decision-making designed to manage two types of uncertainty - the maturity of scientific and clinical knowledge, and the behaviors of other critical stakeholders.

Beneath most lively policy debates sit dry-as-dust theoretical and methodological discussions. Current disputes over the EU Adaptive Pathways initiative(1,2) and the proposed US 21st Century Cures Act(3) may ultimately rest on addressing arcane issues of data curation, standardization, and utilization. Improved extraction of information on the safety and effectiveness of drugs-in-use must parallel adjustments in evidence requirements at the time of licensing. To do otherwise may compromise safety and efficacy in the name of fostering innovation.

// The pharmaceuticals sector provides an archetypical example of proactive public sector risk governance. Unlike ordinary consumer products, drugs may not be marketed without advance regulatory approval. Licensing is based on projections of safety, ef cacy, and acceptable manufacturing quality, with revisions to the conditions of licenses as safety, ef cacy or quality issues arise in use. On 10 October 2014, the OECD and IRGC sponsored a panel on risk governance in pharmaceuticals, with a mandate to describe sources of innovation in pharmaceuticals development and use, to present regulatory, patient and industry perspectives on managing bene ts and risks, and discussing current European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approaches to the management of risks and uncertainty over the full life cycle of drugs. The panelists jointly produced this distillation of presentations and summary of discussion themes.

Confronted with the challenge of improving regulatory performance, many governments in the world are looking for ways to better manage risks, in particular those risks that develop in complex systems, with stakeholders from various sectors, and that are marked by uncertainty. This report includes five authored pieces about: The contribution of transnational private regulation to revisiting risk regulation (Scott), Emerging strategies to manage system-level risks: an examination of private sector, government and non-governmental organization initiative (Yosie), Potential scope and challenges of behaviourally informed regulation (Renn and Florin), and Managing uncertainty in drug development and use, by enhancing adaptability and flexibility in pharmaceuticals regulation (Oye et al.).

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.

The research community and the public require a fast, flexible response to the synthesis of morphine by engineered yeasts, urge Kenneth Oye, Tania Bubela and J. Chappell H. Lawson.